(a) Field of the Invention
The invention relates to bioactive conjugates covalently attached on an implant surface for improving its integration into surrounding tissues.
(b) Description of Prior Art
Devices in the form of plates, nails, pins, screws, and specially formed parts are commonly implanted into the skeletal structure of humans as artificial prosthetic means for permanent replacement of missing structural parts, or as permanent anchoring devices for maintaining a fixed relationship between the portions of a fractured bone. Clearly, in those situations where durability is necessary or desirable, the implanted part should remain permanently adhered to the contacting bone surface. This requirement has been a source of some difficulty in the past, where prosthetic parts composed of high strength materials such as titanium, stainless steel, tantalum, or Vitallium.TM. (an alloy of cobalt, chromium, and molybdenum) have generally been found incapable of forming a strong union with the natural bone structure into which the implantation is made. Highly magnified photographs of sections taken through bone and implant where failure has occurred have revealed what appears to be an absence of coalescence between the artificial and natural parts, and in fact an actual separation between the implant surface and the bone matter adjacent thereto is often apparent.
The use of surgical prosthetic devices, otherwise known as implants, is well known in various surgical applications, such as reconstructive surgery, for example, in the replacement of hip joints or the like. These applications generally involve the use of an implant constructed of metal or alloy which is not substantially corroded or otherwise degraded by body fluids. These prior implants, however, suffer from a number of limitations.
Typically, in the setting of broken bones, metal plates have been used which are secured to either side of the bone fracture. The plates are commonly secured to the bones by screws. While the plate in time becomes encapsulated in bone and body tissue, no bond is formed between the implant and the tissue. If one of the screws comes loose, the patient may have to undergo additional corrective surgery.
Suggestions have been made in the prior art to provide surgical prosthetic devices which are capable of permanent incorporation into the body, usually the bone, with bonding between the implant and the tissues.
In one prior suggestion, there is described a prosthetic device consisting of a metal substrate or base having a thin porous coating of metal overlying and bonded to the surface. The presence of the pores allows the soft or hard tissue to grow into the porous coating of the device and hence achieve mechanical incorporation into the body.
The only method of forming the coating which is described in this prior art suggestion is the technique of plasma or flame spraying onto the metal substrate. The result of this process is a densely adherent layer of the sprayed metal on the substrate metal with no porosity or practically no porosity at the interface between the coating and the substrate and with gradually increasing porosity, including increasing pore size and decreasing density, from the interface to the surface of the coating.
While this technique may be effective in providing a porous coating on a metal substrate, nevertheless the technique results in a very serious drawback in the finished prosthetic device. In tests designed to show the ingrowth of tissue into the coated surface of the device, a pin, having the coating thereon, and after embedding in a bone for a period of time, was subjected to a pull-out test. This pull-out test resulted in shearing at the interface between the coating and the base metal. This result indicates that the overall strength of the device is less than that of the bone. Quite clearly, the provision of a device weaker than the bone to which it is attached could result in failure of the device due to shearing at the interface with harmful and painful consequences for a patient who is treated using such a device.
Another prior art suggestion involves the provision of a prosthetic device constructed of porous ceramic material. This material is structurally weak and attempts to overcome this defect by filling the bulk of the device with resin material, leaving a porous surface area. Although the presence of the resin may increase the strength of the central portion of the device, the surface region remains weak. Further, the presence of resin material degradable by body fluids would lead to unsatisfactory use in the human body. In addition, the maximum pore size for the ceramic is indicated to be 50 microns, and much smaller sizes are preferred. If the pore size were greater than 50 microns, then the structure would become too weak for effective use.
It has been known to anchor surgical implants in bones with the use of cements. It has also been known to improve the anchorage of an implant without using a cement by constructing the implant so as to receive an ingrowth of bone tissue. For example, implants have been provided with a porous surface of a certain depth. However, these porous surface implants have not proven themselves in practice since the mechanical strength of the anchoring surface is greatly affected in an adverse sense. The reason for this weakening of the material is that the pores produce sharp corners and edges in the material. This leads, especially in the case of long-term alternating stresses, to cracks which continue into the solid core of the implant and eventually to fatigue fractures.
Implants have also been constructed with a regular arrangement of bosses and/or depressions in order to improve mechanical adhesion within bones. However, quite apart from the fact that sharp corners and edges have not been avoided in these structures, increased adhesion between the implants and the tissue has not been achieved. This latter failure has occurred because only an insufficient increase of the surface is obtained. As is known, an increase in the anchoring surface is a decisive feature which can influence and improve a bond between the tissue and the anchoring part of the implant which acts as a foreign body therein.
U.S. Pat. No. 3,605,123 in the name of Hahn (Apr. 29, 1969) describes a prosthesis of high structural strength, with a capability of promoting substantially complete integration with the bone structure in which it is implanted.
U.S. Pat. No. 3,855,638 in the name of Pilliar (Dec. 24, 1974) describes a surgical prosthesis of a composite structure consisting of a solid metallic material substrate and a porous coating adhered to and extending at least partially over the surface of the substrate. The porous coating on the surface of the substrate has several parameters which are essential to the provision of a satisfactory device free from the defects of the prior devices.
U.S. Pat. No. 4,272,855 in the name of Frey (Jun. 16, 1981) describes a bone implant with an anchoring surface including a plurality of villi.
However, none of these prior art implants is provided with a chemical coating which would promote a chain of biochemical reactions at the tissue-implant interface, thereby promoting tissue growth, stabilization and integration of the implant.
Substantial progress has been made with regard to implants such as for the restoration of oral tissues, and currently employed techniques rely principally on the use of alloplastic replacement materials. Titanium, titanium-alloy and hydroxyapatite-coated orthopedic and dental implants are widely used in medicine and dentistry for tissue repair, reconstruction and replacement, and as supports for various prostheses. These implants are generally utilized in surgical procedures involving bone, where they are incorporated into this hard, mineralized tissue (`osseointegration`), and in some cases, also traverse soft tissue such as skin or the mucosa of the oral cavity.
In hard biological structures such as teeth (dentin, cementum) and bone, great rigidity and strength are imparted to these tissues by an extensive network of collagen protein fibers that are impregnated with apatitic mineral. Although collagen is by far the most abundant protein in these tissues, other non-collagenous proteins are also secreted by cells and accumulate within their respective extracellular matrices. Although, the exact function of these non-collagenous proteins is unknown, they have recently come under intense scrutiny since experimental results indicate that they may play a critical role in the initiation and regulation of calcification (reviewed by Boskey, Bone Mineral, 6:111-123, 1989 and Gorski, Calcif. Tissue Int., 50:391-396, 1992).
One group of non-collagenous proteins, the phosphoproteins (containing organic phosphorus), and more specifically a dentin phosphoprotein called phosphophoryn and two bone phosphoproteins named osteopontin and bone sialoprotein (reviewed by Butler, Connect. Tissue Res., 23:123-136, 1989 and Butler, J. Biol. Buccale, 19:83-89, 1991), may participate by acting as a seed or regulator of mineral crystal growth and/or by directing cells and their associated functions to specific sites within the tissue. In addition to its co-localization with mineral at early sites of calcification, osteopontin and bone sialoprotein are known to contain the Arg-Gly-Asp (RGD) cell-binding peptide sequence that binds to a plasma membrane integrin receptor and promotes cell attachment (see Telios Pharmaceuticals, Inc., Manual for Summary: 1-10). The presence of this triplet sequence, the distribution of these proteins, and their association with mineral, suggest that these phosphoproteins may have a multifunctional role during mineralized tissue formation whereby they may, firstly, initiate and regulate mineralization, and secondly, direct dynamics by mediating cell attachment to the matrix (McKee et al., Anat. Rec., 234:479-492, 1992 and McKee et al., J. Bone Miner. Res., 8:485-496, 1992).
For an implant to be successful, the intraosseous portion of the implant must undergo osseointegration and a functional junctional epithelium-like seal must form around the transgingival portion (reviewed by McKinney et al., J. Dent. Educ., (Sp. Iss.) 52:696-705, 1988). Any imperfection in these events may lead to the eventual rejection of the implant. The junctional epithelium, in normal conditions, seals the subgingival portion of the tooth from the buccal environment and consists of an epithelial layer, a glycoproteinaceous structure which resembles a basal lamina, and hemidesmosomes (Schroeder, Differentiation of human oral stratified epithelia, S. Karger Publishers, Basel., 1981). The basal lamina and the hemidesmosomes are believed to serve in the attachment of the gingiva to the tooth surface (Schroeder, Helv. Odont. Acta, 13:65-83, 1969), possibly via integrin receptors (Hormia et al., J. Dent. Res., 71:1503-1508, 1992). It has been suggested that laminin (Sawada et al., J. Perio. Res., 25:372-376, 1990) and collagen type VIII (Salonen et al., J. Perio. Res., 26:355-360 1991) are present in the junctional epithelium, the presence of the latter being particularly interesting in that collagen type VIII is not a common component of basement membranes in general. Similarly, the sugar content of the junctional epithelium basal lamina, as visualized by lectin-gold cytochemistry (Zalzal et al., J. Dent. Res., 72:411, 1993), appears to be unique. Just like conventional basement membranes, the basal lamina of the junctional epithelium could play an inductive role in the specialization of the oral epithelium to become bona fide junctional epithelium (reviewed by Timpl, Eur. J. Biochem., 180:487-502, 1989).
The fundamental assumption in each of these situations is that extracellular matrix components of the adjacent tissue (i.e. bone, soft connective tissues or epithelium) allow `bonding` between the non-biological implant and the biological extracellular matrix surrounding the implant. In bone, for example, this bonding region (interface) has been identified, using electron microscopy, as a layer of non-collagenous organic material separating the bone matrix proper from the implant (Steflik et al., J. Biomed. Materials Res., 26:529-545, 1992).
Sukenik, C. N. et al. (J. Biomed. Materials Res., 24:1307-1323, 1990) describes the modulation of cell adhesion by modification of titanium surfaces with covalently attached self-assembled monolayers. However, they do not show the attachment of bioactive conjugates which include biologically active molecules to promote tissue growth, stabilization and integration at the tissue-implant interface.
It would be highly desirable to have a chemical coating for metal implants which would mimic the biological activity of the natural proteins found at the tissue-implant interface in the healing patient with an integrated implant, based on normally-occurring biochemical and physiological mechanisms.
It would be highly desirable to have a chemical coating for metal implants which would promote a chain of biochemical reactions at the tissue-implant interface, thereby promoting tissue growth, stabilization and integration of the implant.